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Overview of Anti-Tumor Peptide Drugs


A variety of newly developed peptide-based drugs are expected to become a promising new class of anti-tumor therapeutic drugs. This blog will give a brief introduction to anti-tumor drugs based on peptide form.
Editor: Cathy Miller Last Updated: 01-Sep-2022

Peptide-based drug design has attracted much interest with the rapid growth of bioinformatics knowledge related to peptides and proteins. In the past, peptide-based drugs were not widely used due to some limitations such as low selectivity and rapid degradation of peptides in biological systems. Excitingly, novel peptide-based therapies emerged in recent years, showing excellent anti-tumor efficacy. A variety of newly developed peptide-based drugs are expected to become a promising new class of anti-tumor therapeutic drugs. This blog will give a brief introduction to anti-tumor drugs based on peptide form.


  1. Peptide drugs for cancer immunotherapy

The treatment of cancer by controlling the function of immune cells is a research hotspot of peptide drugs. PD-L1 is typically overexpressed on many cancer cells and when it binds to PD-1 expressing on activated T cells, the cancer cells can escape from the immune response. Therefore, inhibition of PD-1/PD-L1 interaction could be a method of tumor immunotherapy. Studies have shown that hydrophilic D-type peptide (D-PPA) itself has no cytotoxicity. When blocking the PD-1/PD-L1 interaction, it can inhibit tumor growth in CT26 tumor-bearing mice and prolong their lifespan.


Macrophages are immune cells that play an important role in innate and acquired immunity. The CSF-1/CSF-1R pathway is related to the survival and differentiation of macrophages. In a recent study, a peptide called M2pep[Cys-YeqDPwGVKWWY] was modified to improve specificity against M2 TAMs. The experimental results confirmed that co-encapsulation with CSF-1R siRNA and M2pep could target M2 TAM to remodel into the M1 phenotype and increase anti-tumor immune response.


  1. Apoptosis-related peptide drugs

Certain peptides can induce apoptosis in cancer cells. For example, an anticancer peptide called RA-V (deoxybouvardin) can induce mitochondrial apoptosis in tumor cells, followed by loss of mitochondrial function. Another pentapeptide, Dolastatin 10, was able to induce apoptosis by up-regulating cytochrome C and Bax.


KLA (KLAKLAKLAK) is also one of the pro-apoptotic peptides, which induces programmed cell death by disrupting the mitochondrial membrane. Bioconjugates containing KLA peptides can be used in the development of various anticancer drugs. For example, KLA can bind to the tumor homing peptide IRGD(CRGDKGPDC) to improve the permeability of tumor tissues and cells. The potent anti-tumor effect of the recombinant KLA-IRGd conjugate as well as the high tumor selectivity and low systemic toxicity have been demonstrated in mouse models. These studies may lead to the development of novel targeted PDCS.


Another example of a KLA-based therapy is the penetratin (a cell-penetrating peptide)-KLA conjugate. To overcome the low cellular permeability of KLA peptides, penetratin was linked to KLA peptides via disulfide bonds, resulting in high cellular permeability and cytotoxicity, even at low concentrations. The penetratin-KLA conjugate has little effect on the mitochondria of normal cells, showing its therapeutic potential as a novel peptide conjugate.


  1. Peptides for tumor enrichment

There have also been some new studies describing various methods of targeting tumors with peptides. For example, it was reported that the S-S-bridged cyclic peptide (ALOS-4) is specific for the integrin AVβ3, which is highly expressed in human metastatic melanoma. In this study, ALOS-4 was coupled to the topoisomerase I inhibitor camptothecin. The results showed that the conjugate had potent anti-tumor activity in human metastatic melanoma cells, but low toxicity to normal cells. In addition, a researcher team conjugated the four-branched peptide NT4 to paclitaxel (PTX). NT4 peptides can selectively bind to tumor membrane glycosaminoglycans sulfate. It is highly selective for cancer cells when combined with paclitaxel, and this combination allows it to exhibit more potent anti-tumor activity than paclitaxel alone.


In another study, the tumor targeting of albumin-binding peptides was investigated. In vitro studies, the bioconjugation of DICLPRWGCLW to form a stable albumin complex can play a role in tumor targeting, and also showed high tumor targeting and significantly increased half-life in the SCC7 tumor-bearing mouse model. Based on the positive correlation between albumin uptake and tumor growth, albumin binding is expected to become a novel therapeutic strategy for targeting tumor tissues.


  1. Peptide drugs conjugated with small cytotoxic drugs

Under the concept of drug conjugates, the combination of peptides with cytotoxic drugs or other therapeutic agents can be used to develop peptide-based therapeutic agents.


Several studies have shown that cytotoxic drugs can bind to peptides with additional functions. For example, in anticancer therapy, platinum-based cisplatin chemotherapy is one of the most widely used cancer treatment strategies. However, because of cisplatin resistance, long-term use of cisplatin in patients reduces its efficacy. The use of peptides may be an important way to solve the problems related to drug resistance. When cisplatin is combined with peptides, the binding induces a high accumulation of cisplatin in tumors and metastasis-containing organs and significantly reduces the systemic toxicity of cisplatin.


Several peptide drug conjugations are currently under clinical investigation for the treatment of refractory tumors. On February 27, 2021, Melflufen (Melphalan flufenamide, PEPAXTO®), the first peptide-coupled drug, was approved by FDA for the treatment of multiple myeloma. Because melflufen is highly lipophilic, it is readily ingested by targeted cancer cells. Once internalized, melflufen molecules can be cleaved by aminopeptidase, which is highly expressed in multiple myeloma cells, and release alkylating agent toxic drugs that cause DNA damage and apoptosis in tumor cells. Now, many other forms of peptide-drug conjugates are also under active development as anticancer drugs.


Creative Peptides’ Perspectives

Due to the advantages of peptides, peptide drugs or peptide-drug conjugates have been extensively explored for new drug R&D. Previously, peptide drugs were seen as simply mimicking hormones or endogenous peptides in the body, but they are now being reborn to be designed into new therapies. However, as the limitations of peptide drugs have been solved, the powerful anti-tumor effect of peptide drugs has attracted the attention of researchers and the pipeline layout of more and more companies. Various therapeutic strategies that combine cytotoxic antitumor drugs with functional peptides come to a reality and are expected to be more effective than small-molecule drugs, antibodies, and ADCs.



  1. Blocking of the PD-1/PD-L1 Interaction by ad-Peptide Antagonist for Cancer Immunotherapy.
  2. Tumor-penetrating peptide fused to a pro-apoptotic peptide  facilitates effective gastric cancer therapy.